CN105037380B - Indoles podophyllotoxin derivative, its preparation method, pharmaceutical composition and application - Google Patents
Indoles podophyllotoxin derivative, its preparation method, pharmaceutical composition and application Download PDFInfo
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- CN105037380B CN105037380B CN201510176694.9A CN201510176694A CN105037380B CN 105037380 B CN105037380 B CN 105037380B CN 201510176694 A CN201510176694 A CN 201510176694A CN 105037380 B CN105037380 B CN 105037380B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
The invention discloses a kind of indoles podophyllotoxin derivative, its preparation method, pharmaceutical composition and application.The preparation method of indoles podophyllotoxin derivative shown in formula I disclosed by the invention, is comprised the steps of：In organic solvent, in the presence of alkali, in the presence of condensing agent, the compound as shown in Formula II is subjected to condensation reaction with the compound as shown in formula III.The invention also discloses comprising indoles podophyllotoxin derivative shown in the pharmaceutical composition of indoles podophyllotoxin derivative shown in formula I and formula I prepare for treating cancer medicine in application.The indoles podophyllotoxin derivative of the present invention has good inhibiting tumour cells activity, and its preparation method and post processing are simple and easy to apply, with the good prospect of marketing.
Description
Technical field
The present invention relates to a kind of indoles podophyllotoxin derivative, its preparation method, pharmaceutical composition and application.
Background technology
Podophyllotoxin analogue has multiple use for example antimycotic, antiviral, antitumor etc..Etoposide (VP-16) is made
For the semi-synthetic podophyllotoxin derivative of first listing, it is mainly used in treating ED-SCLC, to acute leukemia, pernicious pouring
Bar knurl, carcinoma of urinary bladder, prostate cancer, stomach cancer, oophoroma etc. are also effective.Its Antitumor Mechanism of podophyllotoxin derivative is main
Have：(1) suppress cellular microtubules polymerization, prevent cell mitogen, it is stuck in mid-term.(2) topoisomerase II is suppressed
(Topo-II) it is active, stable DNA-Topo II- drug molecule compounds are formed, DNA break is caused, causes cell death.
(3) intake of the suppression cell to all kinds of nucleosides such as thymidine, uracil, adenine, guanine, and then suppression cell DNA,
RNA and protein synthesis.There is narrow antitumor spectra, serious gastrointestinal reaction, marrow suppression as Topo II inhibitor in VP-16
The shortcomings of toxic side effects such as system and easily generation drug resistance.So structure of modification is carried out to podophyllotoxin analogues such as VP-16,
Obtain the big emphasis that new antitumor spectra is new type antineoplastic medicine research and development compared with wide, the less compound of toxic side effect.
The content of the invention
The technical problems to be solved by the invention be in order to solve existing podophyllotoxin derivative tumor suppression compose it is narrow,
There are serious bone marrow suppression and gastrointestinal side effect etc., and there is provided a kind of with the entirely different indoles podophyllotoxin of prior art
Plain derivative, its preparation method, pharmaceutical composition and application.The indoles podophyllotoxin derivative of the present invention has good swell
Oncocyte inhibitory activity, its preparation method and post processing are simple and easy to apply, with the good prospect of marketing.
The invention provides the indoles podophyllotoxin derivative shown in a kind of formula I：
Wherein, X is oxygen or nitrogen；R is substituted or unsubstituted C2~C10Heteroaryl, described substituted or unsubstituted C2
~C10Heteroaryl be substituted or unsubstituted indyl；N is 0,1,2,3 or 4；As n=1, X is O；Described substituted Yin
Substitution described in diindyl base refers to be replaced by following one or more substituents：Halogen (preferably fluorine, chlorine, bromine or iodine), C1~C4
Alkyl (preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or the tert-butyl group), C1~C4Alkoxy (preferably
Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy), nitro, amino or hydroxyl,
When substituent is multiple, described substituent is identical or different.
It is preferred that n is 0,1,2 or 3；Described substituent is located at 6 of indyl (for example
Described indyl is preferablyDescribed substituted indyl is preferably
In one aspect of the present invention, the indoles podophyllotoxin derivative shown in formula I, it is preferred that when n is 1,2,3 or 4
When, X is O；When described indyl isWhen n is 0, X is N；When indyls of the R for substitution, described is substituted by
Replaced by halogen, when n is 0, X is O；When indyls of the R for substitution, described is substituted by by C1~C4Alkoxy replaced,
When n is 0, X is N.
In another aspect of the present invention, the indoles podophyllotoxin derivative shown in formula I, it is preferred that when R is indyl
When, X is N；When indyls of the R for substitution, described being substituted by is replaced by halogen, and when n is 0, X is O.
In another aspect of the invention, the indoles podophyllotoxin derivative shown in formula I, it is preferred that n is 0；When R is Yin
Diindyl base is (for example) when, X is N；When indyls of the R for substitution, described is substituted by by halogen
Replace (for example) when, X is O；When indyls of the R for substitution, described substitution
For by C1~C4Alkoxy replace (for example) when, X is N.
Indoles podophyllotoxin derivative shown in described formula I, most preferably, it is following any compound：
Present invention also offers a kind of preparation method of the indoles podophyllotoxin derivative shown in described formula I, its
Comprise the steps of：In organic solvent, in the presence of alkali, in the presence of condensing agent, by the compound as shown in Formula II and such as
Compound shown in formula III carries out condensation reaction as follows；
Wherein, R1For hydroxyl (- OH) or amino (- NH2)；X, R and n definition are the same as those described above.
The method and condition of described condensation reaction can be the such reaction in this area conventional method and condition.It is of the invention special
Not preferred following method and condition：,, will be such as Formula II in the presence of condensing agent and catalyst in the presence of alkali in organic solvent
Shown compound carries out condensation reaction with the compound as shown in formula III.Wherein, the compound as shown in Formula II
Can be to be participated in the form of hydrochloride in reaction.Described organic solvent is preferably halogenated hydrocarbon solvent and/or amide-type is molten
Agent.Described halogenated hydrocarbon solvent is preferably chlorinated hydrocarbon solvent.Described chlorinated hydrocarbon solvent is preferably dichloromethane.
Described amide solvent is preferably N,N-dimethylformamide (DMF).Described condensing agent is preferably 1- (3- diformazan ammonia
Base propyl group) -3- ethyl carbodiimide hydrochlorides (EDCI), 1- hydroxy benzo triazoles (HOBt), 2- (7- azepines BTA) -
N, N, N ', N '-tetramethyl hexafluorophosphoric acid ester (HATU), N, N '-dicyclohexylcarbodiimide (DCC) and diethyl phosphorocyanidate
(DEPC) one or more in, more preferably for 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides (EDCI) and/or
1- hydroxy benzo triazoles (HOBt).Described alkali is preferably organic base.Described organic base is preferably triethylamine.It is described
Catalyst be preferably DMAP (DMAP).The consumption of described catalyst can be the such catalytic reaction in this area
The conventional amount used of agent, it is preferred that the mol ratio of described catalyst and the compound as shown in Formula II is 0.05:1~0.1:1.
Described organic base and the mol ratio of the compound as shown in Formula II are preferably 1:1~3:1, it is more preferably 2:1.Described contracting
Mixture and the mol ratio of the compound as shown in Formula II are preferably 1:1~3:1.The described compound as shown in Formula II with such as
The mol ratio of compound shown in formula III is preferably 1:1~1:3.Described organic solvent and the compound as shown in Formula II
Volume mass than preferably 1mL/g~10mL/g.The temperature of described condensation reaction is preferably 0 DEG C~30 DEG C.It is described
Condensation reaction process can use this area in traditional test methods (such as TLC or HPLC) be monitored, the reaction time
Preferably 1~24 hour.
After described condensation reaction terminates, it is preferred that may also include the operation of post processing.The method of described post processing and
Condition can post-process conventional method and condition for this area, and the reaction solution after preferably condensation reaction is terminated adds water and quenched
Go out, using esters solvent (such as ethyl acetate) or halogenated hydrocarbon solvent (such as dichloromethane) extraction (3 times), organic layer is successively
Washed with saturated sodium bicarbonate aqueous solution, water and salt solution (saturated sodium-chloride water solution) are washed, (such as anhydrous with suitable drier
Sodium sulphate) organic layer is dried, filtering removes solvent, is separated through column chromatography (dichloromethane/ethyl acetate system gradient elution) pure
Change produces target compound.
Present invention also offers a kind of pharmaceutical composition, it includes indoles podophyllotoxin derivative shown in above-mentioned formula I
And pharmaceutically acceptable excipient.
According to therapeutic purposes, aforementioned pharmaceutical compositions can be made to various types of administration unit dosage forms, for example：Aqueous point
Powder, liquid, Gel miles, syrup, elixir, medicine slurry, suspension, aerosol, controlled release agent, quick-dissolving agent, effervescent agent, freeze-dried, piece
Agent, powder, pill, complete sugar-coat, capsule, sustained release agent, extension releasing agent, pulse controlled release agent, multiparticulates agent discharge immediately
Agent.
Prepared present invention also offers the indoles podophyllotoxin derivative shown in described formula I for treating cancer
Medicine in application.Described cancer is preferably lung cancer, carcinoma of mouth, liver cancer or leukaemia.Described lung cancer is preferably
Non-small cell lung carcinoma.Described carcinoma of mouth is preferably human oral cavity epithelial cancer.The tumour cell of described cancer is preferably
Non-small cell lung carcinoma cell, human oral cancer epithelial cell, human liver cancer cell or mice sperm malformation test.Described people is non-
Small cell lung cancer cell is preferably Non-small cell lung carcinoma cell line A549.Described human oral cancer cell is preferably population
Chamber cancer epithelial cell strain KB.Described human liver cancer cell is preferably HepG2 cell lines.The white blood of described mouse lymph
Sick cell is preferably mouse lymphocyte leukemia cell line L1210.
In the present invention, room temperature refers to 0~30 DEG C.Ice bath refers to -5~0 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and produce the present invention each preferably
Example.
Agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is：
The indoles podophyllotoxin derivative of the present invention has good inhibiting tumour cells activity, and its preparation method is with after
Processing is simple and easy to apply, with the good prospect of marketing.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.
In following embodiments, such as it is not specifically noted, its rate of charge generally refers to mol ratio.Room temperature refers to 0~30 DEG C.Ice
Bath refers to -5~0 DEG C.
1. the synthesis of key intermediate：
Embodiment 1
4 beta-aminos -4 4 β of the synthesis-chloroacetyl amido -4 of-demethyl epipodophyllotoxin ' '-demethyl epipodophyllotoxin
Synthesis
At room temperature, 4 '-demethyl epipodophyllotoxin (10g, 25mmol) is added into chloroacetonitrile (15mL, 250mmol),
The 0.15mL98% concentrated sulfuric acids, stirring is added dropwise, it can be seen that insoluble matter dissolves and has white solid generation rapidly, adds 50mL isopropanols
Dilute solid, suction filtration, filter cake continues to be washed 2 times with 100mL isopropanols point, after be washed with water to neutrality.Vacuum drying chamber is placed to dry
40 DEG C of dry 4h, obtain white solid powder 10g, yield：84%.
ESI-MS：476(M+H+)/493(M+H3O+).
1HNMR(DMSO-d6)：8.60 (1H, dd, NH), 8.20 (exchanges of 1H, d, OH heavy water), 6.89 (1H, d, 5H), 6.52
(1H,d,8H),6.23(2H,s,H-2′,6′),6.00(2H,d,-OCH2O),5.19(1H,dd,H-4),4.5(1H,d,H-1),
4.34(1H,t,H-11α),3.79(1H,t,H-11β),4.19(2H,s CH2),3.89(6H,s,2’,6’-O-CH3),3.21
(1H,dd,s,H-1),3.15(1H,m,3H).
Embodiment 2
4 beta-aminos -4 '-demethyl epipodophyllotoxin preparation
By 4 β-ChloroacetYl -4 ' addition of-demethyl epipodophyllotoxin (10g, 21mmol) is into 50mL glacial acetic acid, liter
Temperature adds thiocarbamide (2.4g, 31mmol) to 80 DEG C, and the interior reaction solutions that can be seen of about 10min have muddiness to be changed into clarification, maintain 80 DEG C
2.5h is stirred, there is white solid generation, is not regenerated to precipitation, stops reaction, 50mL glacial acetic acid is continuously added, solid is diluted,
Suction filtration, filter cake is washed three times with absolute ether 150mL, is transferred in vacuum drying chamber and is dried, 4 beta-aminos -4 '-demethyl table ghost
Mortar toxin hydrochloride 6.85g yields：84%.
ESI-MS：400(M+H+).
1HNMR(DMSO-d6)：8.60(2H,s,-NH2Heavy water, which is exchanged, to disappear), 8.20 (1H, s, OH heavy water, which are exchanged, to disappear),
7.20(1H,d,5H),6.80(1H,d,8H),6.19(2H,s,H-2′,6′),6.00(2H,d,-OCH2O),4.78(1H,d,H-
4),4.57(1H,d,H-1),4.34(2H,m,H-11α,β),3.60(6H,s,2’,6’-O-CH3),3.08(1H,m,H-3).
2. the synthesis of target compound
Mode one：
At room temperature, by compound III：EDCI：DMAP(1.5eq：1.5eq：0.1eq) add to the dichloro of appropriate drying
In methane, after stirring 0.5h, 4 '-demethyl epipodophyllotoxin (DMEP, 1eq) and triethylamine (2eq) are added into reaction solution,
When TLC detection reactions are no longer carried out, add water and reaction is quenched.Extracted 3 times with appropriate dichloromethane, combined dichloromethane layer is used
Saturation NaHCO3Solution, water, salt solution (saturated sodium-chloride water solution) washing organic layer.Organic layer anhydrous sodium sulfate drying mistake
At night, anhydrous sodium sulfate is filtered to remove, filtrate decompression is evaporated, gained solid is through column chromatography, with dichloromethane/ethyl acetate (DCM/
EA) target compound is afforded for eluent gradient.
Mode two：
At room temperature, by compound III：EDCI：HOBt(1.5eq：1.5eq：1.5eq) add to dry dichloromethane
In, after stirring 0.5h, 4 '-demethyl epipodophyllotoxin (DMEP, 1eq) and triethylamine (2eq), TLC inspections are added into reaction solution
When survey reaction is no longer carried out, add water and reaction is quenched.Extracted 3 times with appropriate dichloromethane, combined dichloromethane layer uses saturation
NaHCO3Solution, water, salt solution (saturated sodium-chloride water solution) washing organic layer.Organic layer is stayed overnight with anhydrous sodium sulfate drying, mistake
Anhydrous sodium sulfate is filtered out, filtrate decompression is evaporated, gained solid is with dichloromethane/ethyl acetate (DCM/EA) through column chromatography
Eluent gradient affords target compound.
Mode three：
At room temperature, by compound III：EDCI：HOBt(1.5eq：1.5eq：1.5eq) add to the N, N- of appropriate drying
In dimethylformamide, after stirring 0.5h, 4 beta-amino 4- deoxidation -4 '-demethyl epipodophyllotoxin hydrochloric acid are added into reaction solution
Salt (1eq) and triethylamine (2eq), when TLC detection reactions are no longer carried out, add water and reaction are quenched.3 are extracted with appropriate ethyl acetate
Secondary, combined ethyl acetate layer uses saturation NaHCO3Solution, water, salt solution (saturated sodium-chloride water solution) washing organic layer.Organic layer
Stayed overnight with anhydrous sodium sulfate drying, be filtered to remove anhydrous sodium sulfate, filtrate decompression is evaporated, gained solid is through column chromatography, with dichloro
Methane/ethyl acetate (DCM/EA) is that eluent gradient affords target compound.
Embodiment 3
The preparation of 4 β-(indoles -2- acetoxyl groups) -4- deoxidations -4 '-demethyl epipodophyllotoxin (I-1)
DCM 3mL, indole-2-carboxylic acid (364mg, 2.25mmol) feeds intake and post-processed according to shown in method two, obtains white
Color solid 120mg, yield is 21.4%.
ESI-MS：566(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 11.98 (s, 1H), 7.71 (d, J=8Hz, 1H), 7.50 (d, J=8.4Hz,
1H), 7.30 (t, J=7.2Hz, 2H), 7.11 (t, J=8Hz, 1H), 6.97 (s, 1H), 6.58 (s, 1H), 6.41 (s, 2H),
6.01 (d, J=2.8Hz, 2H), 5.72 (s, 1H), 5.44 (d, J=5.6Hz, 1H), 4.78 (t, J=3.6Hz, 1H), 4.65
(d, J=5.6Hz, 1H), 4.39 (t, J=8Hz, 1H), 4,23 (t, J=10.8Hz, 1H), 3.64 (s, 6H), 3.36 (dd, J=
5.6Hz,5.6Hz,1H).
Embodiment 4
The preparation of 4 β-(indoles -2- acetamidos) -4- deoxidations -4 '-demethyl epipodophyllotoxin (I-2)
DMF 3mL, indole-2-carboxylic acid (242mg, 1.5mmol) feeds intake and post-processed according to shown in method three, obtains white
Solid 175mg, yield is 32.3%.
ESI-MS：565(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 11.54 (s, 1H), 8.65 (d, J=8.4Hz), 8.17-7.88 (m, 1H),
7.60 (d, J=8Hz, 1H), 7.45 (d, 8.4Hz, 1H), 7.22 (t, J=5.6Hz, 1H), 7.19 (d, J=1.2Hz, 1H),
7.03 (t, J=8Hz, 1H), 6.86 (s, 1H), 6.58 (s, 1H), 6.30 (s, 1H), 6.00 (d, J=12Hz, 1H), 5.72 (d,
J=0.4Hz, 1H), 5.50 (dd, J=4.8Hz, 4.8Hz, 1H), 4.56 (d, J=5.2Hz, 1H), 4.38 (t, J=8Hz,
1H), 4.04 (dd, J=6.8Hz, 1H), 3.66 (s, 3H), 3.47 (dd, J=5.2Hz, 5.2Hz, 1H), 3.07 (m, 1H),
(m, the 1H) of 2.89 (s, 2H), 2.73 (s, 1H), 1.98 (d, J=9.2Hz, 1H), 1.17
Embodiment 5
It is prepared by 4 β-(5- fluoro indole -2- acetoxyl groups) -4- deoxidations -4 '-demethyl epipodophyllotoxins (I-3)
DCM 4mL, 5- fluoro indole -2- formic acid (215mg, 1.2mmol) feeds intake and post-processed according to shown in method two, obtains
White solid 220mg, yield is 27%.
ESI-MS：584(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 12.12 (s, 1H), 7.48 (m, 2H), 7.30 (d, J=1.2Hz, 1H), 7.17
(m, 1H), 6.97 (s, 1H), 6.57 (s, 1H), 6.40 (s, 2H), 6.01 (d, J=2.4Hz, 2H), 4.78 (d, J=3.2Hz,
1H), 4.64 (d, J=5.6Hz, 1H), 4.39 (t, J=8Hz, 1H), 4.23 (t, J=6.4Hz, 1H), 4.04 (dd, J=
7.2Hz,7.2Hz,1H),3.64(m,6H),2.86-2.83(m,1H).
Embodiment 6
It is prepared by 4 β-(5- fluoro indole -2- acetamidos) -4- deoxidations -4 '-demethyl epipodophyllotoxins (I-4)
DMF 4mL, 5- fluoro indole -2- formic acid (269mg, 1.5mmol) feeds intake and post-processed according to shown in method three, obtains
White solid 170mg, yield is 30.4%.
ESI-MS：583(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 11.67 (s, 1H), 8.70 (d, J=8.4Hz, 1H), 8.16 (s, 1H), 7.44
(m, 2H), 7.22 (d, J=2.4Hz, 1H), 7.05 (m, 1H), 6.86 (s, 1H), 6.58 (s, 1H), 6.30 (s, 2H), 6.00
(s, 1H), 5.97 (s, 1H), 5.72 (s, 1H), 5.50 (m, 1H), 4.56 (d, J=5.2Hz, 1H), 4.37 (t, J=8.4Hz,
1H),3.81(m,1H),3.66(s,6H),3.47-3.42(m,1H).
Embodiment 7
It is prepared by 4 β-(5- chloro-indole -2- acetoxyl groups) -4- deoxidations -4 '-demethyl epipodophyllotoxins (I-5)
DCM 5mL, 5- chloro-indole -2- formic acid (235mg, 1.2mmol) feeds intake and post-processed according to shown in method two, obtains
White solid 116mg, yield is 20%.
ESI-MS：600(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 12.21 (s, 1H), 7.77 (d, J=1.6Hz, 1H), 7.51 (d, J=
8.8Hz, 1H), 7.30 (m, 2H), 6.97 (s, 1H), 6.57 (s, 1H), 6.40 (s, 2H), 6.01 (d, J=2.4Hz, 2H),
5.72 (s, 1H), 5.43 (d, J=4.8Hz, 1H), 4.78 (s, 1H), 4.64 (d, J=5.2Hz, 1H), 4.39 (t, J=
7.6Hz, 1H), 4.23 (t, J=8.4Hz, 1H), 3.64 (s, 6H), 2.87-2.83 (m, 1H)
Embodiment 8
It is prepared by 4 β-(5- chloro-indole -2- acetamidos) -4- deoxidations -4 '-demethyl epipodophyllotoxins (I-6)
DMF 5mL, 5- chloro-indole -2- formic acid (293mg, 1.5mmol) feeds intake and post-processed according to shown in method three, obtains
White solid 214mg, yield is 37.1%.
ESI-MS：599(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 11.77 (s, 1H), 8,74 (d, J=8.4Hz, 1H), 8.16 (s, 1H), 7.95
(s, 1H), 7.67 (s, 1H), 7,45 (d, J=8.8Hz, 1H), 7.20 (m, 2H), 6.86 (s, 1H), 6.58 (s, 1H), 6.30
(s, 2H), 6.00 (d, J=11.6Hz, 2H), 5.51-5.48 (m, 1H), 4.56 (d, J=5.2Hz, 1H), 4.37 (t, J=
8Hz, 1H), 3.80 (t, J=11.2Hz, 1H), 3.66 (s, 6H), 3.47-3.42 (m, 1H)
Embodiment 9
It is prepared by 4 β-(5- methoxy-Indole -2- acetoxyl groups) -4- deoxidations -4 '-demethyl epipodophyllotoxins (I-7)
DCM 3mL, 5- methoxy-Indole -2- formic acid (288g, 1.5mmol) feeds intake and post-processed according to shown in method two,
Faint yellow solid 240mg is obtained, yield is 41.9%.
ESI-MS：596(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 11.84 (s, 1H), 7.39 (d, J=9.2Hz, 1H), 7.21 (s, 1H), 7.14
(d, J=2Hz, 1H), 6.91 (m, 2H), 6.57 (s, 1H), 6.39 (s, 2H), 6.01 (d, J=3.2Hz, 2H), 5.43 (d, J=
6.4Hz, 1H), 4.77 (t, J=5.2Hz, 1H), 4.64 (d, J=5.2Hz, 1H), 4.38 (t, J=8Hz, 1H), 4.22 (t, J
=10.8Hz, 1H), 3.77 (s, 3H), 3.63 (s, 6H), 2.86-2.83 (m, 1H)
Embodiment 10
It is prepared by 4 β-(5- methoxy-Indole -2- acetamidos) -4- deoxidations -4 '-demethyl epipodophyllotoxins (I-8)
DMF 3mL, 5- methoxy-Indole -2- formic acid (288g, 1.5mmol) feeds intake and post-processed according to shown in method three,
Faint yellow solid 232mg is obtained, yield is 40.6%.
ESI-MS：595(M+Na+).
1H NMR(400MHz,DMSO-d6) δ 11.39 (s, 1H), 8.60 (d, J=8.4Hz, 1H), 8.15 (s, 1H), 7.34
(d, J=8.8.Hz, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.87-6.84 (m, 2H), 6.58 (s, 1H), 6.31 (s, 2H),
6.00 (d, J=11.6Hz, 2H), 5.72 (s, 1H), 5.52-5.48 (m, 1H), 4.56 (d, J=4.8Hz, 1H), 4.37 (t, J
=8.4Hz, 1H), 3.80 (t, J=10.4Hz, 1H), 3.75 (s, 3H), 3.66 (s, 6H), 3.45 (dd, J=5.2Hz,
5.2Hz,1H),3.07-3.05(m,1H).
Embodiment 11
The preparation of 4 β-(indoles -3- formyloxies) -4- deoxidations -4 '-demethyl epipodophyllotoxin (I-9)
DCM 4mL, indole -3-carboxylic acid (242mg, 1.5mmol) feeds intake and post-processed according to shown in method two, obtains white
Solid 150mg, yield is 27.6%.
ESI-MS：566(M+Na+), 582 (M+K+).
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.27(s,1H),8.20–8.14(m,2H),7.44(d,J
=7.5Hz, 1H), 7.19-7.09 (m, 2H), 6.88 (s, 1H), 6.59 (s, 1H), 6.31 (s, 2H), 6.00 (d, J=
11.7Hz, 2H), 5.52 (dd, J=8.3,4.8Hz, 1H), 4.56 (d, J=5.1Hz, 1H), 4.40 (t, J=8.1Hz, 1H),
3.89-3.79 (m, 1H), 3.67 (s, 6H), 3.45 (dd, J=14.4,5.2Hz, 1H), 3.04 (dd, J=25.2,7.3Hz,
1H).
Embodiment 12
The preparation of 4 β-(indoles -3- formamidos) -4- deoxidations -4 '-demethyl epipodophyllotoxin (II-10)
DMF 3mL, indole -3-carboxylic acid (242mg, 1.5mmol) is located according to being fed intake shown in amide-type synthetic method three with after
Reason, obtains white solid 95mg, yield is 17.5%.
ESI-MS：565(M+Na+).
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.31(s,1H),8.23–8.10(m,3H),7.44(d,J
=7.6Hz, 1H), 7.15 (t, J=14.9Hz, 2H), 6.88 (s, 1H), 6.58 (s, 1H), 6.31 (s, 2H), 5.99 (d, J=
11.7Hz, 2H), 5.53 (s, 1H), 4.56 (s, 1H), 4.42 (s, 1H), 4.05 (dd, J=18.9,11.9Hz, 1H), 3.83
(t, J=9.5Hz, 1H), 3.66 (s, 6H), 3.03 (d, J=8.0Hz, 1H)
Embodiment 13
The preparation of 4 β-(indoles -3- acetoxyl groups) -4- deoxidations -4 '-demethyl epipodophyllotoxin (I-11)
DCM 5mL, indole -3-carboxylic acid (242mg, 1.5mmol) feeds intake and post-processed according to shown in method two, obtains white
Solid 150mg, yield is 27.6%.
ESI-MS：566(M+Na+), 582 (M+K+).
1H NMR(400MHz,DMSO-d6) δ 10.94 (s, 1H), 7.55 (d, J=7.8Hz, 1H), 7.37 (d, J=
8.1Hz, 1H), 7.32 (s, 1H), 7.10 (t, J=7.5Hz, 1H), 7.01 (t, J=7.1Hz, 1H), 6.95 (s, 1H), 6.53
(s, 1H), 6.32 (s, 2H), 5.99 (s, 2H), 5.49 (d, J=5.9Hz, 1H), 4.77-4.73 (m, 1H), 4.59 (d, J=
5.4Hz, 1H), 4.41-4.32 (m, 1H), 4.20 (dd, J=10.6,8.4Hz, 1H), 3.98 (s, 2H), 3.62 (s, 6H),
3.32 (dd, J=14.3,5.4Hz, 1H), 2.88-2.74 (m, 1H)
Embodiment 14
The preparation of 4 β-(indoles -3- butyryl acyloxies) -4- deoxidations -4 '-demethyl epipodophyllotoxin (I-12)
DCM 3mL, indole -3-butyric acid (302mg, 1.49mmol) feeds intake and post-processed according to shown in method one, obtains white
Color solid 466mg, yield is 63.8%, purity：92.26%.
ESI-MS：608(M+Na+), 624 (M+K+).
1H-NMR(400MHz,DMSO-d6) δ 10.72 (s, 1H), 7.45 (d, J=7.8Hz, 1H), 7.32 (d, J=
8.1Hz, 1H), 7.06 (dd, J=14.6,4.7Hz, 2H), 6.95 (t, J=7.4Hz, 1H), 6.91 (s, 1H), 6.56 (s,
1H), 6.23 (s, 2H), 6.09 (d, J=3.5Hz, 1H), 6.01 (d, J=17.2Hz, 2H), 4.56 (d, J=5.2Hz, 1H),
4.31 (t, J=7.9Hz, 1H), 3.84 (t, J=12.0Hz, 1H), 3.64 (s, 6H), 3.21 (d, J=5.2Hz, 1H), 3.08-
2.97 (m, 1H), 2.70 (t, J=7.4Hz, 2H), 2.43 (dd, J=14.7,7.4Hz, 2H), 1.96-1.87 (m, 2H)
Embodiment 15
The preparation of 4 β-(indoles -3- amide-based smalls) -4- deoxidations -4 '-demethyl epipodophyllotoxin (I-13)
DMF 3mL, indole -3-butyric acid (302mg, 1.49mmol) feeds intake and post-processed according to shown in method three, obtains white
Color solid 88mg, yield is 15.0%, purity：90.50%.
ESI-MS：607(M+Na+).
1H NMR(400MHz,CDCl3) δ 8.06 (s, 1H), 7.58 (d, J=7.6Hz, 1H), 7.36 (d, J=8Hz, 1H),
7.19 (t, J=3.2Hz, 1H), 7.10 (t, J=4Hz, 1H), 6.98 (s, 1H), 6.72 (s, 1H), 6.50 (s, 1H), 6.29
(s, 2H), 5.97 (d, J=4.8Hz, 2H), 5.61 (d, J=6.8Hz, 1H), 5.21 (t, J=6.4Hz, 1H), 4.51 (d, J=
4.4Hz, 1H), 4.37 (t, J=8.4Hz, 1H), 3.75 (m, 6H), 2.91 (m, 3H), 2.69 (m, 1H), 2.31 (t, J=
7.2Hz,2H),2.11(m,2H),1.36(m,2H).
The compound of effect example 1 suppresses the activity experiment of tumour cell
1st, experiment purpose
In vitro with the indoles podophyllotoxin derivative of the mtt assay measuring present invention to the thin of human tumor cell line
Cytotoxicity
2nd, instrument and equipment
(1)CO2Cell culture incubator, PHARMA SCIENTIFIC.
(2) enzyme-linked immunosorbent assay instrument, Labsystems, wellscan, MK.2.
(3) the double superclean bench of vertical one side, Suzhou Decontamination Equipment Plant.
(4) inverted biologic microscope, 37XB/37 × BTV, the factory of Shanghai optical instrument six.
3rd, experiment material and preparation
(1) cell line：Human lung cancer (A549), human liver cancer (HepG2), human oral cancer (KB), mouse leukemia cell
(L1210), cell line is purchased from cell institute of the Chinese Academy of Sciences.
(2) DMEM cell culture mediums (GIBCO)：Containing 10% inactivation newborn calf serum, (Shanghai match is limited up to biological medicine company
Company)；L- glutaminases (import is dispensed, SANGON)；Sodium Pyruvate；1×105U.L-1Penicillin, 100mg.L-1Streptomysin；Nothing
Bacterium is filtered, 4 DEG C of preservations.
(3) 0.25% trypsin solutions (Trypsin)：Purchased from Invitrogen companies, -20 DEG C of preservations.
(4) phosphate buffer (PBS)：NaCl 8g, KCl 0.2g, Na2HPO41.15g, KH2PO40.2g, is dissolved in 1L double
Steam water, 121 DEG C of autoclave sterilization 20min, 4 DEG C of preservations.
(5) MTT (AMRESCO) solution：5mg/mL solution is made into PBS.
(6) lysate：Contain SDS10g, isobutanol 5mL, concentrated sulfuric acid 0.12mL per 100mL deionizations distilled water.
(7) sample：Indoles podophyllotoxin derivative of the present invention.
(8) reference substance：Etoposide injection, purchased from Hengrui Medicine Co., Ltd., Jiangsu Prov..
4th, experimental method
Indoles podophyllotoxin derivative is measured to the cytotoxicity of above-mentioned tumor cell line by mtt assay.Specific steps
It is as follows：
(1) cell culture：1. cell is taken out from liquid nitrogen, thawed rapidly in 37 DEG C of water-baths, cell is in sterile working
Moved into platform in 10mL sterile centrifugation tubes, plus 6mL DMEM cell culture mediums, 1000 revs/min centrifuge 5 minutes.Abandoning supernatant,
5-6mL DMEM cell culture mediums are added in precipitation, dropper piping and druming makes it be moved into after suspending in Tissue Culture Flask, puts 37 DEG C of cells
In incubator.2. next day, cell is taken out from incubator, discards DMEM cell culture mediums in cell bottle and (remove K562 (the chronic marrows of people
The suspension cells such as former leukemia cell line and L1210 (mice sperm malformation test strain)), add 5-6mL DMEM cell culture
Base, puts in 37 DEG C of cell culture incubators.3. the next day, cell is taken out from incubator, discards DMEM cell culture mediums in cell bottle and (remove
The suspension cells such as K562 (the former leukemia cell line of the chronic marrow of people) and L1210 (mice sperm malformation test strain)), add PBS
(PH7.4) 2-3mL rocks cleaning, outwells to repeat after PBS solution and once cleans.The pancreas of 3-5 drops 0.25% is added in blake bottle
Protein enzyme solution is rocked uniformly, and capping is placed in 37 DEG C of cell culture incubators 3 minutes or so, finds cell certainly in micro- Microscopic observation
Cultivate and depart from bottle wall, plus DMEM cell culture medium 2mL, dropper, which is blown and beaten, makes cell completely disengage from after bottle wall, and 2 are moved into respectively and is done
In net blake bottle, add DMEM cell culture mediums 5-6mL piping and druming uniformly, be placed in 37 DEG C of cell culture incubators.K562 (the chronic marrows of people
Former leukemia cell line) and the suspension cell such as L1210 (mice sperm malformation test strain) take out 1-2mL suspension, move respectively
Enter in 2 clean blake bottles, add DMEM cell culture medium 5-6mL, be placed in 37 DEG C of cell culture incubators.4. the next day, repeat to walk
Suddenly operation 3..In whole incubation, attached cell do not allow growth it is overstocked, suspension cell remains logarithmic growth
Phase.
(2) sample preparation：Sample is dissolved in dimethyl sulfoxide, the solution that concentration is 10mg/mL is obtained.Made again with PBS
Gradient dilution, it is respectively 1000 μ g/mL, 100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL to obtain concentration
Dilute sample.
It is prepared by reference substance：Etoposide injection is made into gradient dilution with PBS, obtain concentration be respectively 1000 μ g/mL,
100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL dilution reference substance.
(3) sample diluted and reference substance are added in flat 96 orifice plate, per the μ L of hole 10, every is made two parallel surveys
Examination.DMSO is accordingly made to add in plate after gradient dilution, control is used as.
(4) cell in exponential phase is taken, cell digests through pancreatin and is suspended in containing 10% calf serum after washing
DMEM culture mediums in, dye exclusive method meter viable count through trypan blu e, and adjust cell suspending liquid density to 2 × 105Cell/
mL。
(5) in flat 96 orifice plate, 90 μ L cells are added per hole, in 37 DEG C, 5%CO2Overnight incubation in cell culture incubator.
(6) flat 96 orifice plate of cell will be added in 37 DEG C, 5%CO2Cultivated 48 hours in cell culture incubator.
(7) 20 μ L 5mg/mLMTT solution are added in every hole, continues to be incubated 3~4 hours in incubator.
(8) 100 μ L lysates are added per hole, continues the incubated overnight in incubator, makes generation Jia Za crystal fully molten
Solution.Determine 492nm absorbance values.
(9) comparative survival rate of cells after compound processing is calculated according to absorbance value.Calculation formula is as follows：
(10) IC of the compound to each tumour cell is calculated by software50。
Wherein, numbering I-1 and VP16 are before the Chinese patent application CN201410172493.7 applying date in table 1.1
Flown to survey Activity Results by inventor Sun Ya, and numbering I-2~I-14 and VP16 are in Chinese patent application in table 1.2
After the CN201410172493.7 applying date Activity Results are surveyed by inventor's Yao Li rosy clouds.
Table 1.1MTT methods survey Activity Results
Table 1.2MTT methods survey Activity Results
According to the effect example of the present invention, for the indoles podophyllotoxin derivative shown in the formula I of the present invention
Structure-activity relationship is analyzed：
In the podophyllotoxin derivative shown in formula I-a：
1st, during R group α and β connection 4- -4 '-demethyl epipodophyllotoxin of hydroxyl, the inhibitory activity to tumour cell has
Influence.I-1 is compared with I-9, and β are better than to better than I-9, the i.e. α substitutions of inhibitory action I-1 for surveying four kinds of tumor cell lines.
2nd, electron donating group is introduced in R group to have an impact activity.I-1 is compared with I-3, I-5, I-7,5 methoxyl groups on indole ring,
The inhibitory action of four kinds of tumor cell lines is not greatly improved when halogen replaces, 5 enhance pair when being methoxy substitution
The inhibitory action of L1210 cell lines, introducing chlorine enhances the inhibitory activity to HepG2, KB and L1210.3rd, chain length shadow is connected
Ring antitumor activity.I-9 is compared with I-11, I-12, and carbochain, which increases, to be strengthened the inhibitory action of HepG2, A549 and KB cell, but
Inhibitory action reduction to L1210 cell lines.
Resulting all compounds are removed has inhibitory action to cell lines such as HepG2, KB and L1210, and to VP-16
Invalid A549 cell lines also have inhibitory action.
In the podophyllotoxin derivative shown in formula I-b：
1st, substituted or unsubstituted indyl (R group) is with α and β connection 4- -4 '-demethyl epipodophyllotoxin of amino
When, the inhibitory activity to tumour cell has an impact.I-2 is compared with I-10, and surveyed tumor cell line KB and A549 cell lines are pressed down
Make of quite, better than I-2, i.e. β substitutions of inhibitory action I-10 to HepG2 and L1210 cells are better than α.2nd, substitution or
Electron donating group is introduced on unsubstituted indyl (R group) to have an impact activity.I-2 is compared with I-4, I-6, I-8, indoles
Slightly have reduction on ring when 5 methoxyl groups, halogens substitution to the inhibitory action of four kinds of tumor cell lines, 5 for methoxy substitution when
The inhibitory action to HepG2 and L1210 cell lines is enhanced, the inhibitory activity that halogen reduces four kinds of cell line is introduced.3rd, even
Chain link effect length antitumor activity.I-10 is compared with I-13, and carbochain increases all to have dropped to the inhibitory action of four kinds of cell line
It is low.
Resulting all compounds are removed has inhibitory action to cell lines such as HepG2, KB and L1210, and to VP-16
Invalid A549 cell lines also have inhibitory action.
Claims (16)
1. the indoles podophyllotoxin derivative shown in a kind of formula I：
Wherein, X is oxygen or nitrogen；R is substituted or unsubstituted C2~C10Heteroaryl, described substituted or unsubstituted C2~C10
Heteroaryl be substituted or unsubstituted indyl；N is 0,1,2,3 or 4；As n=1, X is O；Described substituted indyl
Described in substitution refer to be replaced by following one or more substituents：Halogen, C1~C4Alkyl, C1~C4Alkoxy,
Nitro, amino or hydroxyl, when substituent is multiple, described substituent is identical or different.
2. the indoles podophyllotoxin derivative shown in formula I as claimed in claim 1, it is characterised in that when described takes
When being substituted by described in the indyl in generation is replaced by halogen, described halogen is fluorine, chlorine, bromine or iodine；When described substitution
Indyl described in be substituted by by C1~C4Alkyl when replacing, described C1~C4Alkyl be methyl, ethyl, just
Propyl group, isopropyl, normal-butyl, isobutyl group or the tert-butyl group；Being substituted by by C described in the described substituted indyl1~C4's
When alkoxy replaces, described C1~C4Alkoxy for methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy,
Isobutoxy or tert-butoxy.
3. the indoles podophyllotoxin derivative shown in formula I as claimed in claim 1, it is characterised in that described indyl
ForAnd/or, described substituted indyl is
4. the indoles podophyllotoxin derivative shown in formula I as claimed in claim 1, it is characterised in that shown in formula I
In indoles podophyllotoxin derivative, when n is 1,2,3 or 4, X is O；When described indyl isWhen n is 0, X
For N；When indyls of the R for substitution, described being substituted by is replaced by halogen, and when n is 0, X is O；When indyls of the R for substitution,
Described is substituted by by C1~C4Alkoxy replaced, n be 0 when, X is N.
5. the indoles podophyllotoxin derivative shown in formula I as claimed in claim 1, it is characterised in that shown in formula I
In indoles podophyllotoxin derivative, when R is indyl, X is N；When indyls of the R for substitution, described is substituted by by halogen
Element is replaced, and when n is 0, X is O.
6. the indoles podophyllotoxin derivative shown in formula I as claimed in claim 1, it is characterised in that shown in formula I
In indoles podophyllotoxin derivative, n is 0；When R is indyl, X is N；When indyls of the R for substitution, described is substituted by
When being replaced by halogen, X is O；When indyls of the R for substitution, described is substituted by by C1~C4Alkoxy when replacing, X is
N。
7. the indoles podophyllotoxin derivative shown in formula I as claimed in claim 1, it is characterised in that it appoints to be following
One compound：
8. a kind of preparation side of the indoles podophyllotoxin derivative shown in formula I as described in any one of claim 1~7
Method, it is characterised in that it is comprised the steps of：,, will be such as Formula II in the presence of condensing agent in the presence of alkali in organic solvent
Shown compound carries out condensation reaction as follows with the compound as shown in formula III；
R1For hydroxyl or amino；X, R and n definition are as described in any one of claim 1~7.
9. preparation method as claimed in claim 8, it is characterised in that the method for described condensation reaction is：In organic solvent,
In the presence of alkali, in the presence of condensing agent and catalyst, by the compound as shown in Formula II and the compound as shown in formula III
Carry out described condensation reaction.
10. preparation method as claimed in claim 9, it is characterised in that the compound as shown in Formula II is with hydrochloride
Form participate in reaction；Described organic solvent is halogenated hydrocarbon solvent and/or amide solvent；Described condensing agent is
1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides, 1- hydroxy benzo triazoles, 2- (7- azepines BTA) -
N, N, N ', N '-tetramethyl hexafluorophosphoric acid ester, N, one kind in N '-dicyclohexylcarbodiimide and diethyl phosphorocyanidate or
It is a variety of；Described alkali is organic base；Described catalyst is DMAP；Described catalyst with as shown in Formula II
The mol ratio of compound is 0.05:1~0.1:1；The mol ratio of described organic base and the compound as shown in Formula II is 1:1~
3:1；The mol ratio of described condensing agent and the compound as shown in Formula II is 1:1~3:1；The described chemical combination as shown in Formula II
The mol ratio of thing and the compound as shown in formula III is 1:1~1:3；Described organic solvent and the compound as shown in Formula II
Volume mass ratio be 1mL/g~10mL/g；The temperature of described condensation reaction is 0 DEG C~30 DEG C；And/or, described condensation
The time of reaction is 1~24 hour.
11. a kind of pharmaceutical composition, it is characterised in that it includes Yin shown in the formula I as described in any one of claim 1~7
Diindyl class podophyllotoxin derivative and pharmaceutically acceptable excipient.
12. the indoles podophyllotoxin derivative shown in a kind of formula I as described in any one of claim 1~7 is preparing use
Application in the medicine for the treatment of cancer.
13. application as claimed in claim 12, it is characterised in that described cancer is lung cancer, carcinoma of mouth, liver cancer or white blood
Disease.
14. application as claimed in claim 13, described lung cancer is Non-small cell lung carcinoma；
And/or, described carcinoma of mouth is human oral cavity epithelial cancer.
15. application as claimed in claim 13, the tumour cell behaviour non-small cell lung cancer cell of described cancer, human mouth
Cancer epithelial cell, human liver cancer cell or mice sperm malformation test.
16. application as claimed in claim 15, described Non-small cell lung carcinoma cell behaviour non-small cell lung cancer cell strain
A549；
And/or, described human oral cancer cell is human oral cancer epithelial cell strain KB；
And/or, described human liver cancer cell is HepG2 cell lines；
And/or, described mice sperm malformation test is mouse lymphocyte leukemia cell line L1210.
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| CN105801592A (en) * | 2016-03-25 | 2016-07-27 | 遵义医学院 | Preparation method of podophyllotoxin picolinic formic ether derivative and application of derivative to anti-leukemia drug |
| CN107652300B (en) * | 2017-09-20 | 2019-08-09 | 辽宁大学 | The podophyllotoxin analogue of the structure of triazinone containing 1,2,4- and its application |
| CN108530460A (en) * | 2018-06-12 | 2018-09-14 | 遵义医学院 | Podophyllotoxin-Lonidamine conjugate and its synthetic method and medical usage |
| CN109678870A (en) * | 2018-12-28 | 2019-04-26 | 济南爱思医药科技有限公司 | A kind of biologically active podophyllotoxin derivative and preparation method thereof |
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| CN113214281B (en) * | 2021-05-19 | 2022-05-17 | 济宁市第一人民医院 | Synthesis of benzene sulfonamide phenylbutyrate podophyllotoxin ester derivatives and application of benzene sulfonamide phenylbutyrate podophyllotoxin ester derivatives in anticancer drugs |
| CN114085230B (en) * | 2021-09-24 | 2024-02-06 | 遵义医药高等专科学校 | N-succinic acid monosubstituted indole (azole) spliced podophyllotoxin compound and preparation method and application thereof |
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| US5332811A (en) * | 1989-09-12 | 1994-07-26 | The University Of North Carolina At Chapel Hill | Etopside analogs |
| CN1068330A (en) * | 1991-07-03 | 1993-01-27 | 国家医药管理局上海医药工业研究院 | 4-nitrogen replacement-4-deoxidation-4 '-demethylated podophyllotoxin derivative and synthetic method thereof |
| CN1139593C (en) * | 2000-08-18 | 2004-02-25 | 国家医药管理局上海医药工业研究院 | 3 alpha-bromoepipodophyllotoxin, its position-4 substituted derivative and preparing process thereof |
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| CN100334090C (en) * | 2005-02-02 | 2007-08-29 | 南京医科大学 | Pyridines podophyllotoxin compounds and their preparation method and use in preparation of pesticides |
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| Publication number | Publication date |
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| CN105037379A (en) | 2015-11-11 |
| CN105037379B (en) | 2017-12-19 |
| WO2015161745A1 (en) | 2015-10-29 |
| CN105037380A (en) | 2015-11-11 |
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